Traditional approaches to cancer therapies have focused on targeting and destroying cancer cells. However, direct access to the cancer cells is often limited. More recent strategies have focused on targeting tumor vasculature, rather than the cancer cells directly, to suppress the formation of new blood vessels and/or to destroy established tumor vasculature, and eventually starve the tumor and send it into regression [Matter, Drug Discov. Today, 6, 1005-1024 (2001); Thorpe, et al., Cancer Res. 63, 1144-1147 (2003); Folkman, Semin. Oncol. 29, 15-18 (2002); Garde, et al., Anti-Cancer Drugs, 18, 1189-1200 (2007)].
Tumor vasculature has an abnormal wall structure and the endothelial cells in the angiogenic vessels within solid tumors express several proteins that are present in very low quantities or totally absent in established blood vessels, including aminopeptidase N isoform CD13 (APN/CD13). Jain, Nat. Med. 9:685-693 (2003).
The NGR (Asn-Gly-Arg) peptide motif is a ligand for APN/CD13. This peptide motif homes inside tumors, offering a means to target therapeutic and diagnostic agents into solid tumors by linking the therapeutic or diagnostic agent to the NGR peptide. NGR-containing peptides have been proven useful for delivering cytotoxic drugs, apoptotic peptides, and cytokines [such as tumor necrosis factor (TNF)] to tumor vasculature. Curnis, et al., Cancer Res. 62, 867 (2002); Curnis, et al., J. Clin. Invest. 110, 475 (2002).
Both linear and disulfide-bridged cyclic peptides containing the NGR motif have been used to deliver various anti-tumor compounds and viral particles to tumor vessels, with the cyclic versions showing more than a 10 fold higher anti-tumor activity than their linear counterparts. Colombo, et al., J. Biol. Chem., 277(49), 47891-47897 (2002).
The disulfide-bridged cyclic peptides containing the NGR motif are not stable and breakdown under certain physiological conditions in cellular environments. Accordingly, there is a pressing need to permanently cyclized compounds having the NGR peptide motif to target APN/CD13. The invention is directed to these, as well as other, important needs.